Varicella-zoster virus (VZV) establishes latency in human sensory and cranial nerve ganglia during primary infection (varicella), and the virus can reactivate and cause zoster after primary infection. The virus is difficult to grow to high titers in cell culture and difficult to isolate from clinical specimens since it is very unstable. This year we showed that neurons derived from human embryonic stem cells are highly permissive for infection by varicella-zoster virus (VZV). VZV is highly cell associated when grown in cell culture and requires a much higher number of particles (4,000- to 20,000-fold) than herpes simplex virus (HSV) to infect cells. In contrast, VZV is highly infectious to humans by airborne transmission. Neurons are major targets for VZV in humans. The virus establishes latency in human neurons and reactivates to produce infectious virus. Using neurons derived from human embryonic stem cells and cell-free wild-type VZV, we demonstrated that neurons are nearly 100 times more permissive for WT VZV infection than very-early-passage human embryonic lung cells or MRC-5 diploid human fibroblasts, the cells used for vaccine production or virus isolation. The peak titers achieved after infection were about 10-fold higher in human neurons than in MRC-5 cells, and the number of viral genome copies for a given virus particle was about 100-fold lower for VZV in human neurons compared with MRC-5 cells. Thus, VZV may not necessarily be less infectious in cell culture than other herpesviruses; instead, the cells previously used to grow the virus in vitro may have been suboptimal. Furthermore, based on electron microscopy, neurons infected with VZV produced fewer defective or incomplete viral particles than MRC-5 cells. Our data suggest that neurons derived from human embryonic stem cells may have advantages compared to other cells for studies of VZV pathogenesis, for obtaining stocks of virus with high titers, and for isolating VZV from clinical specimens.